Biosimilar or Similar Biologics (Indian context) is a biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product, as defined by World Health Organization (WHO).1 The United States Food and Drug Administration (FDA) emphasizes “no clinically meaningful differences” from an existing FDA-approved reference product”.2
Both biologics and biosimilars are typically large, complex proteins having therapeutic efficacy, produced using living cells or derived from living cells by recombinant DNA or controlled gene expression methods. They can be monoclonal antibodies, soluble receptors, growth factors, or hormones.(European Medicines Agency).3 As the synthesis pathway of the reference biologic is proprietary, the biosimilars are developed by analysing the reference biologic molecule and reverse engineering a feasible synthesis pathway with relatively lesser cost of production. Hence, biosimilars have the potential to reduce the overall treatment cost due to improvements and increased efficiency in the production process. But they are not exactly identical to reference biologics because of the complex structure, which may be affected by minor alteration in sequences and factors involved in post-translational modifications. (Ghosh PK., 2017).4
There are guidelines developed by the WHO, European Medicines Agency, or US Food and Drug Administration specifically for the review and approval of these products. In India, “Guidelines on Similar Biologic: Regulatory Requirements for Marketing Authorization in India” (updated: 2016), prepared by Central Drugs Standard Control Organization (CDSCO) which is the Indian regulatory body for pharmaceuticals and the Department of Biotechnology (DBT), are followed.5 The biosimilars undergo an abbreviated approval process by demonstration of similarity/equivalence to the reference biologics in terms of physicochemical, molecular and biological characterisation; antigen binding ability and avidity; and clinical safety and immunogenicity. (Isaacs J et al., 2017)6
Trastuzumab (Herceptin®), a recombinant antibody developed and patented by Genentech (later acquired by Roche in 2009), is widely used to treat breast cancer characterized by over-expression of Human Epidermal growth factor Receptor 2 (HER2/neu) in the cells. The antibody targets HER2 blocks downstream signalling pathways leading to cell death.
A series of granted patents, which were filed as divisional and continuation applications claiming priority from 3rd May 1999, claim for compositions and methods of purification of trastuzumab. When the innovator company loses their monopoly over the inventions after the fixed term of patent, it opens the window of opportunities for other interested companies in developing similar products with reduced production cost. As the patents of interest (US6339142B17, US6489447B18, US6417335B19, US7074404B210, US7531645B211) are about to expire in May 2019, many global players in the pharmaceutical industry have attempted to develop biosimilars for trastuzumab.
Among them, Trastuzumab-dkst (MYL-1401O; branded as ‘Ogivri’), codeveloped by Mylan and Biocon, an Indian biopharmaceutical company is the first biosimilar of Trastuzumab which got approved by regulatory bodies to treat particular malignancies of breast cancer. Drugs Controller General of India (DCGI) approved Trastuzumab-dkst in 2013. Later, the drug got approval from FDA in 2017 and European Medicines Agency in 2018 for the treatment of HER2-positive metastatic cancer. Other biosimilars which have got FDA approval are Celltrion’s trastuzumab-pkrb (Herzuma), Samsung Bioepis’s trastuzumab-dttb (Ontruzant), Pfizer’s trastuzumab-qyyp (Trazimera).
In India, Trastuzumab was launched by Roche in the year 2002. Indian patent (205534) on Trastuzumab lapsed in 2013 due to non-payment of renewal fees and Roche decided not to pursue it and its related divisional applications. In 2014, Biocon and Mylan launched Trastuzumab biosimilar (branded as ‘CANMAb’ and ‘Hertraz’) in 2014, with a price reduced to half from that of the innovator drug, which is in the ‘National List of Essential Medicines’. Roche challenged the abbreviated process in the approval mechanism adopted by the Drugs Controller General of India in the Delhi High Court. But, the court held that marketing of the biosimilar product by Biocon and Mylan for the treatment of early breast cancer, metastatic cancer and gastric cancer can be allowed. In April 2017, the Competition Commission of India released its order opening an investigation against Roche for blocking the entry of biosimilars of Trastuzumab, after receiving a complaint from the two companies about Roche’s anti-competitive behaviours to maintain its monopoly over the drug.
Besides this business tug-of-war scenario, patentability of the biosimilar is a million dollar question. The novelty and inventive step of biosimilar products are questionable. The biosimilar with the desired therapeutic effect can either be a sub-sequence of the original biologic sequence or a longer sequence containing original sequence as sub-sequence. In the case of Trastuzumab, the biosimilar has not been patented and the low-cost drug could not be commercialized by other companies before the lapse of Roche’s trastuzumab patent in India. Still, the patents are active in other countries till May 2019. The claims in the patents of interest are sufficiently broad to restrict the patentability of the biosimilars. However, any formulation comprising the biosimilar, process of production of the biosimilar, method of treatment using the biosimilar, mode of administration of the biosimilar, dosage regime using the biosimilar can be patented, provided they satisfy the criteria for patentability – Novelty, Inventive step and utility.
Claim 1, an independent product claim, mentions a composition of the drug. The specific property of the antibody is that it has the ability to bind HER2. This claim covers all the antibody molecules which have active site to target HER2, despite the variations in their amino acid sequences. The key receptor to be targeted in the case of breast cancer is HER2, since the over-expression of HER2 protein leading to over-growth of breast cells. The therapeutic efficacy of trastuzumab lies in its HER2-binding ability and avidity. Any biosimilar with such desired efficacy is included in this claim.
And, the claimed mixture also comprises of one or more polypeptide variants, which are contaminants, in an amount less than about 25%. It can be inferred from the description that ‘acidic variant’ refers to a sequential variant having at least 80% identical sequence with the anti-HER2 antibody and is more acidic (e.g. de-amidated) than the antibody molecule of interest. Hence, the purity range of the composition has been claimed broadly as more than about 75%.
The dependent claim (claim 2) covers all the carriers, which are pharmaceutically accepted, including buffers, antioxidants, preservatives, low molecular weight polypeptides, proteins, hydrophilic polymers, aminoacids, carbohydrates and/or non-ionic surfactants, as mentioned in the description.
The dependent claim (Claim 3) specifically mentions the anti-HER2 antibody as humMAb4D5-8, the light chain and heavy chain sequences of which have been given in the figures (Fig. 2A and Fig. 2B).
US7074404B2 claims a composition with higher level of purity, which undergoes a purification process using cation exchange chromatography, thus reducing the amount of acidic variants less than about 13%. The methods/process of purification have been claimed in other divisional and continuation patents (US6489447B1, US6417335B1, US7531645B2).
When the patents held by Roche for trastuzumab, its production and purification processes expire, it is expected that biosimilars would hit the market leading to a substantial reduction in overall treatment cost of blood cancer. Hitherto in India, drug makers namely Zydus Cadila, Dr Reddy’s Laboratories, Intas Pharmaceuticals have launched their versions of Trastuzumab biosimilars under the brand names – Vivitra, Hervycta and Eleftha respectively. The latest biosimilar ‘Eleftha’ which has been launched very recently (April 2019), is claimed to be bringing down the cost of breast cancer treatment by nearly 65 %.
To conclude, emerging developments and usage of Trastuzumab biosimilars hold a promise to improve the accessibility and affordability of the cancer drug to the needy patients. And, India has firmly established itself as a global market player by producing them as well as being a huge market for them. The well-grounded regulatory guidelines and patent system in India encourage researchers and investors in the thriving ecosystem of biosimilars/similar biologics.
- Ghosh, P. K. (2017). Similar biologics: global opportunities and issues. Journal of Pharmacy & Pharmaceutical Sciences, 19(4), 552-596.
- Isaacs, J., Gonçalves, J., Strohal, R., Castañeda-Hernández, G., Azevedo, V., Dörner, T., & McInnes, I. (2017). The biosimilar approval process: how different is it?. Considerations in Medicine, 1(1), 3-6.